This invention generally relates to formulations of paclitaxel and more particularly to methods of making formulations of paclitaxel.
Paclitaxel is a natural product which has been shown to possess cytotoxic and antitumor activity. Indeed, paclitaxel may be among the most active single agent for ovarian and breast cancers. This compound is found in small concentrations in the Taxus brevifolia species such as the Pacific yew tree among other Taxus species. While having an unambiguous reputation of tremendous therapeutic potential, paclitaxel as a therapeutic agent has some patient related drawbacks. These stem, in part, from its extremely low solubility in water, which makes it difficult to provide in suitable dosage form. Because of paclitaxel's poor aqueous solubility, the current approved clinical formulation consists of a 6 mg/ml solution of paclitaxel in 50% polyoxyethylated castor oil (CREMOPHOR EL™) and 50% dehydrated alcohol. Am. J. Hosp. Pharm. 48:1520-24 (1991). In some instances, severe reactions, including hypersensitivity, occur in conjunction with the CREMOPHOR™ administered in conjunction with paclitaxel to compensate for its low water solubility. As a result of the incidence of hypersensitivity reactions to the commercial paclitaxel formulations and the potential for paclitaxel precipitation in the blood, the formulation must be infused over several hours. In addition, patients must be pretreated with steroids and antihistamines prior to the infusion.
In response to the hypersensitivity related to the CREMOPHOR™, the increasing recognition of paclitaxel's promise as an antineoplastic, and the undesirability of having to infuse the paclitaxel over several hours, there remains a need to develop improved formulations of the paclitaxel which can be administered as bolus injections.
It is therefore an object of the present invention to provide compositions of the paclitaxel without the solubilizing agent, CREMOPHOR™ which is present in the commercial formulation.
It is another object of the present invention to provide methods for producing the porous dry powder formulations of paclitaxel or docetaxol.
It is another object of the present invention to provide compositions providing enhanced dissolution of paclitaxel or docetaxol in a formulation suitable for administration by a variety of routes, including, but not limited to, parenteral, mucosal, oral, and topical administration, for local, regional, or systemic effect.
It is further object of the present invention to provide paclitaxel compositions for administration as a bolus injection instead of by infusion.